Osteoradionecrosis (ORN) is major complication of cancer therapy that causes facial disfigurement, tooth loss, significant morbidity, debility and diminished quality of life. Factors that make the jaw highly susceptible to ORN are still unclear. Guided by our previous work demonstrating that osteogenesis and bone regenerative properties of human bone mesenchymal stem cells are skeletal site-dependent according to embryological site of origin, we will elucidate underlying radiation-induced cellular events that dysregulate jaw bone healing after irradiation. We hypothesize that radiation disparately regulate jaw osteoclast-osteoblast balance to promote necrosis. We will determine how differential radiation-induced hypoxia accelerates jaw ORN. Understanding the responsiveness of bone mesenchymal stem cells to irradiation is critical to development of preventive therapies that will improve quality o life of cancer survivors.